Amyloid-beta peptides of various lengths (i.e. amyloid-beta 42 and 40) and their accumulation in amyloid-beta plaques are known to play a central role in the pathogenesis of Alzheimer's disease. However, amyloid-beta is normally produced in the brain of healthy individuals throughout life. This may present important issues when designing effective and safe therapeutic approaches against Alzheimer's disease (AD). My laboratory has obtained compelling data showing that administration of amyloid-beta 42, when used at low concentrations, presumably neighboring those found in the normal brain, leads to enhancement of long-term potentiation (LTP), a widely studied cellular model of learning and memory, and post-tetanic potentiation, a type of short- term plasticity that is believed to be an indication of presynaptic function. Picomolar concentrations of amyloid- beta 42 were also able to enhance contextual fear memory and reference memory. Finally, preliminary experiments have shown that depletion of endogenously produced amyloid-beta through antibodies against murine amyloid-beta or through siRNA against murine APP dramatically reduced LTP and hippocampal- dependent memory. Thus, the overall hypothesis of this proposal is that amyloid-beta itself is a critical positive-modulator of synaptic plasticity and memory within the normal CNS. The following three specific aims will be investigated: a) to determine if amyloid-beta is a critical positive modulator of LTP and hippocampal-dependent memory; b) to determine if APP metabolism is altered following tetanic stimulation and memory training, promoting the transient generation of increased amounts of amyloid-beta; c) to determine the mechanisms on how amyloid-beta enhances hippocampal synaptic plasticity and memory. The consequences of our findings go beyond their therapeutic implications, having also relevance for studying the AD pathogenesis and normal learning.